Total Intravenous Anesthesia and
Target-Controlled Infusion
BRIAN J. ANDERSON AND JAMES HOUGHTON
Pharmacokinetic and Pharmacodynamic Principles
Pediatric Pharmacokinetic Parameter Sets
The Target Concentration
Linking Pharmacokinetics with Pharmacodynamics
Pharmacodynamic Interaction Models
Traditional Methods
Response Surface Models
Depth of Anesthesia Monitoring
Common TIVA Drugs
Achieving the Target Concentration in a Multicompartment Model
The Target-Controlled Infusion
THE MOST COMMON INDICATIONS for total intravenous anesthesia (TIVA)
techniques in children are as follows: those at risk for malignant
hyperthermia (in whom inhalational agents are contraindicated);
children with a high risk of postoperative nausea and vomiting,
brief radiologic or painful procedures when rapid recovery is
needed (e.g., magnetic resonance imaging, bone marrow aspiration,
gastrointestinal endoscopy); frequent repeated anesthesia (e.g.,
radiation therapy); major surgery to control the stress response;
neurosurgical procedures to assist with control of intracranial
pressure and for cerebral metabolic protection; spinal instrumenta-
tion requiring evoked motor and auditory brain potentials; and
children in need of airway procedures (e.g., bronchoscopy).1–3
Total intravenous (IV) sedation and anesthesia are used in pediatric
intensive care, but propofol is contraindicated for prolonged use
in very sick or young children because of the risk of developing
propofol infusion syndrome (PRIS).4–13
Pharmacokinetic and
Pharmacodynamic Principles
The goal of pharmacologic treatment is a desired response, known
as the target effect. An understanding of the concentration-response
relationship (i.e., pharmacodynamics [PD]) can be used to predict
the target concentration required to achieve this target effect in
a typical child.14 Pharmacokinetic (PK) knowledge (e.g., clearance
[CL], volume [V]) then determines the dose that will achieve the
target concentration. Calculation of the dose for a drug where
the PK disposition can be described using a one-compartment
model with first-order elimination can be readily calculated:
Loading dose = V × Target Concentration
Maintenance Dose = CL × Target Concentration
However, most drugs used in anesthesia require two or more
compartments to describe their disposition and although the
principles for drug dosing calculation are the same, calculations
8 
A Practical Approach in Children
Drug Delivery
Infusion Regimes
Establishing TIVA after an Inhalational Induction
Practical Approaches for Some Clinical Scenarios
Common Manual Propofol Infusion Schemes
Common Manual Opioid Infusion Schemes
Ready Mixes
are complicated by two or more clearances and volumes (see
below).
Although the parameters used in PK and PD equations (known
as models) for many drugs are published, the values may vary
substantively from child to child. Several covariates have been
identified to more accurately predict the dose for a particular
child, including weight, age, sex, pathology, drug interactions,
and pharmacogenomics. Current pumps used for TIVA incorporate
weight and age to predict the typical drug dose and infusion rate
for a specific patient.15
The use of TIVA for propofol is a good example of “pharmacol-
ogy in action.” The target effect (level of general anesthesia) for
propofol has been defined (e.g., bispectral index [BIS] 50–55),
the target (plasma) concentration to achieve this level of anesthesia
is known (e.g., propofol 4 mg/L) and its PK in children is well
described. Advanced concepts in PK modeling and computer
technology have led to sophisticated delivery systems that facilitate
anesthesia given by the IV route. Further advances involving
feedback from receptor organs have also been developed for
children.16,17 Target-controlled infusion (TCI) devices or “smart
pumps” are an example of a sophisticated delivery system that
may be directed at either plasma (Cp) or effect-site (Ce) drug
concentration. These computerized pumps are a considerable
advance over earlier manual techniques for children18,19 that targeted
only the Cp of the drug. However, they require input of both
PK and PD parameters and a lack of robust PK-PD estimates and
variability in the parameter estimates limit the current accuracy
of TCI in children under 3 years of age.20
PEDIATRIC PHARMACOKINETIC PARAMETER SETS
TCI techniques use propofol and remifentanil as the principal
drugs for induction and maintenance of anesthesia. Popular
pediatric programs used for propofol infusion targeting a plasma
concentration are based on data from Marsh21 and Gepts,22 Kataria,19
Short,23 Rigby-Jones,24 Schuttler,25 Murat,26 Saint-Maurice,27
Coppens28 or Absalom (Paedfusor).29 These parameter sets are
commonly termed “models” and named after the author who
177
178 A Practice of Anesthesia for Infants and Children

TABLE 8.1 Propofol Parameter Estimates for a 20-kg Child

Kataria Marsh21 & Schuttler Rigby-Jones Murat Saint Maurice Coppens
Parameter et al.19 Gepts22 Paedfusor29 Short et al.23 & Ihmsen25 et al.24 et al.26 et al.27 et al.28
V1 (L) 10.4 4.56 9.16 8.64 7.68 11.68 20.6 14.44 3.48
V2 (L) 20.2 9.28 18.98 10.8 20.74 26.68 19.4 35.6 4.68
V3 (L) 164 58.04 116.58 69.4 264.82 223.86 121.74 168 19.02
CL (L/minute) 0.68 0.542 0.568 0.836 0.56 0.444 0.98 0.62 0.78
Q2 (L/minute) 1.16 0.51 1.044 1.22 1.036 0.32 1.34 1.24 2.04
Q3 (L/minute) 0.52 0.192 0.384 0.34 0.46 0.268 0.4 0.22 0.66

Performance of these models differed markedly during the different stages of propofol administration. Most models underestimated propofol concentration 1 minute after the
bolus dose, suggesting an overestimation of the initial volume of distribution. Not all models tested were within the accepted limits of performance (median performance error,
bias <20% and median absolute performance error, precision <30%). The model derived by Short and colleagues performed best32 in children 3 to 26 months.

12
Kataria19 Schuttler25
Marsh21 Rigby-Jones24
10 Paedfusor29 Murat26
Short23 Saint-Maurice27
Concentration (mg/L)

8 Coppens28

0
0 10 20 30 40 50
Time (minutes)

FIGURE 8.1  Simulated time-concentration profiles for propofol using differing parameter sets are shown. A 3-mg/
kg bolus was administered and the infusions were administered as for an adult (10-8-6 regimen, see text). (From
Anderson BJ. Pharmacology of pediatric TIVA. Rev Colomb Anestesiol. 2013;41:205-214. Used with permission.)

reported them (e.g., the Kataria model). Parameter estimates (e.g.,
CL; intercompartment clearance, Q; central volume of distribution,
V1; peripheral volume of distribution, V2) are different for each
parameter set (Table 8.1). Although parameter estimates are different
for each author, most predict similar concentrations for the same
infusion regimen (Fig. 8.1).
Covariate influences that contribute variability to the param-
eters, such as the severity of illness are often unaccounted for—for
example, the volume of the central compartment is increased in
children after cardiac surgery.24 Even weight or age, the most
common sources of variability,30 may be omitted from parameter
estimates. Both the administration method (IV bolus or infusion)31
and the collection of venous blood for assay rather than arterial
blood will influence the PK parameter estimates in the early phase
when the drug is moving into the effect-site compartment. Time-
concentration profiles and context-sensitive half-lives will differ
depending on which parameter set is used.32
There is a paucity of validation studies for these differing
parameter sets.28 The Paedfusor model29 is reported to have a
median performance error, bias (MDPE) of 4.1% and a median
absolute performance error, precision (MDAPE) of 9.7% in children
between 1 and 15 years of age.29 A more recent study concluded
that all parameter sets except that based on the Marsh model
performed acceptably in children between 3 and 26 months.32
Others have described a poor fit for the Kataria model, despite
the fact that it is the most widely used model.33 However, clearance
(expressed as liters per hour per kilogram) decreases with age and
MDPE is minimized at low CL and exaggerated at greater values.
Evaluating models outside the age range in which their parameter
sets were determined will increase the bias and worsen the precision
of the model.
Adult remifentanil PK parameters34 continue to be used in
TCI devices for patients of all ages, despite an increasing knowledge
regarding the pharmacology of this drug in children.35 There is
an element of safety with this approach because both volume of
distribution36 and clearance (expressed as milliliters per minute
per kilogram)37 decrease with increasing age and the elimination
half-life is small with a constant context-sensitive half-life. The
greater volume of distribution in children reduces the peak
concentrations of remifentanil after bolus dosing; the increased
clearance in children results in a smaller plasma concentration
when infused at adult rates expressed as mg/minute per kilograms.
Remifentanil PK can be described in all age groups by simple
application of an allometric size model (see Chapter 7).37 This
 Total Intravenous Anesthesia and Target-Controlled Infusion 179

100

8
80

Bispectral index
60

40 Child
Obese child
Adult
20

0
0.1 1 10
Propofol Concentraion (mg/L)

FIGURE 8.2  The propofol concentration and its relationship with bispectral index in children and adults. (Data from
Coppens MJ, Eleveld DJ, Proost JH, et al. An evaluation of using population pharmacokinetic models to estimate
pharmacodynamic parameters for propofol and bispectral index in children. Anesthesiology 2011;115:83-93; and
Chidambaram V, Venkatasubramanian R, Sadhasivam S, et al. Population pharmacokinetic-pharmacodynamic
modeling and dosing simulation of propofol maintenance anesthesia in severely obese adolescents. Pediatr Anesth.
2015;25:911-923.)

standardized clearance of 2970 mL/minute per 70 kg is similar to
that reported by others in children36,38 and adults.34,39 The smaller
the child, the greater the clearance when expressed as milliliters
per minute per kilogram. Owing to these enhanced clearance
rates, smaller (younger) children will require larger infusion rates
of remifentanil than larger (older) children and adults to achieve
equivalent blood concentrations.
THE TARGET CONCENTRATION
The target concentration is the concentration desired at the effect
site. The plasma and effect-site concentrations are the same at
steady state. The target concentration depends on the desired
effect. This effect is determined by an understanding of the
concentration-response relationship of the drug. This will differ
with age, pathology, drug interactions, and stimulus. The target
concentration may vary depending on the magnitude of the desired
effect. A remifentanil target of 2 to 3 µg/L is adequate for
laryngoscopy, 6 to 8 µg/L for laparotomy and 10 to 12 µg/L
might be sought to ablate the stress response associated with
cardiac surgery.40
A propofol concentration of 2 to 3 mg/L is an appropriate
target for sedation and 4 to 6 mg/L is adequate for anesthesia.
The target effect-site propofol concentrations for both the loss
and return of consciousness in children, 2.0 ± 0.9 mg/L and
1.8 ± 0.7 mg/L, respectively, (mean ± standard deviation) are
similar to those reported in adults.41,42 The relation between drug
concentration and effect is commonly described by the Hill
equation (see Eq. 7.19)43:
Emax ⋅ CeN
Effect = E 0 − Eq. 8.1,
( EC 50N + Ce N )
where E0 is the baseline level of consciousness (e.g., BIS = 100),
Emax is the maximum response, EC50 the concentration at half
this maximum response, Ce the concentration in the effect compart-
ment, and N defines the steepness of the slope.
Jeleazcov et al.44 have described propofol PD in children 1 to
16 years using BIS where E0 was estimated as 93.2, Emax 83.4,
EC50 5.2 mg/L, and N 1.4. This relationship is very similar to
that described in obese children.45 The equilibration rate constant
(keo) between the plasma and effect compartment was 0.6/minute
(T1/2keo 1.15 minutes). Children may have a slightly lower sensitivity
to propofol than adults (Fig. 8.2),33 although this difference may
be due to PK rather than PD factors.46 The Kataria parameter
set is known to underpredict concentration as age increases,
consistent with allometric scaling. When this parameter set is
used to estimate PD parameters, older children appear to require a
smaller concentration to maintain anesthesia47; this is a PK effect
and not a PD effect.48
Maintenance infusion requirements for propofol in neonates
differ substantively from those in older infants and children. These
may be attributed to differences in PK and/or PD. In terms of
the kinetics, the clearance of propofol in neonates is reduced
compared with older infants; clearance decreases with decreasing
postmenstrual age owing to immature enzyme clearance systems.49
To develop a dosage scheme for propofol infusion rates in infants
and children, the adult dosage scheme was adapted to the require-
ments in the younger population by observing the total number
and time of administration of boluses and time to awakening
from propofol in infants younger than 3 years (n = 2271) (Table
8.2).50 The predicted infusion rates for the first 10 minutes in
neonates are large (24 mg/kg per hour; 400 µg/kg per minute),
values that should be used cautiously because of the danger of
an overdose if the infusion continues beyond 10 minutes. Delayed
awakening, hypotension, and an increased incidence of bradycardia
have been reported in neonates and infants.50 Propofol can cause
profound hypotension in neonates and PK-PD relationships in
this age group remain elusive.51
LINKING PHARMACOKINETICS WITH PHARMACODYNAMICS
A simple situation in which drug effect is directly related to
concentration does not mean that drug effects parallel the time
180 A Practice of Anesthesia for Infants and Children

keo Propofol (per minute)

TABLE 8.2 Propofol Dose Requirements in Children Younger 2.5
keo Propofol = 1.03 × e–(0.12 × age)
Than 3 Years of Age 2.0 R 2 = 0.44
Time 0-3 3-6 6-9 9-12 1-3 1.5
(minutes) months months months months years
1.0
0–10 24.3 19.7 15.3 14.8 12.1
10–20 20.4 15.2 12.3 11.9 9 0.5
20–30 15.1 12 9 9 6 0.0
30–40 12 9 6 6 6 0 2 4 6 8 10 12 14 16 18
40–50 9 6 6 6 6
A Age (years)
50–60 6 6 6 6 6

Infusion rates are expressed as milligrams per kilogram per hour.

7

Tpeak Propofol (minutes)

(Adapted from Steur RJ, Perez RS, De Lange JJ.. Dosage scheme for propofol in
children under 3 years of age. Paediatr Anaesth. 2004;14:462-467.)
course of concentration. This occurs only when the concentration
is low in relation to EC50. In this situation, the half-life of the
drug may correlate closely with the half-life of drug effect.
A plasma concentration-effect plot can form a hysteresis loop
because of a delay in effect. Hull et al.52 and Sheiner et al.53
introduced the effect compartment concept for muscle relaxants.
A single first-order parameter (T1/2keo) describes the equilibration
half-time:
T1 2 keo = Ln( 2) keo Eq. 8.2
This mathematical trick assumes the concentration in the central
compartment is the same as that in the effect compartment at
equilibration, but that a time delay exists before drug reaches the
effect compartment. The concentration in the effect compartment
is used to describe the concentration-effect relationship.54
Adult T1/2keo values are well described—for example, morphine
16 minutes; fentanyl 5 minutes; alfentanil 1 minute; propofol 3
minutes. This T1/2keo parameter is commonly incorporated into
TCI pumps to achieve a rapid effect-site concentration.
There are few estimates of the T1/2keo for propofol in children
using simultaneous PK-PD modeling. An estimate of 1.86 min
(95% confidence interval [CI] 1.16–2.31) was reported in healthy
children 2 to 12 years,55 and 1.2 minutes (95% CI 0.85–2.1) in
obese children.45 We might expect a smaller T1/2keo with decreasing
age based on size models.56 Faster half-times in children can be
accounted for by considering the physiologic time that scales to
a power of 1 457:
( )
14
T1 2 keoChild = T1 2 keo ADULT × WT 70 Eq. 8.3
An increasing T1/2keo with age (linked to weight) has been described
for propofol in children (Fig. 8.3).44 Similar results have been
demonstrated for sevoflurane and BIS in patients 3 to 71 years.58
If unrecognixed, this will result in excessive dose in a young child
if the effect site is targeted and peak effect (Tpeak) is anticipated
to be later than it actually is because it was determined in a
teenager or adult (Fig. 8.4).
When both PK and PD data are collected simultaneously and
parameters for both models are estimated together, then the model
is described as “integrated.” PK estimates should not be used in
conjunction with PD estimates from a different data set without
a few “fudge factors.” Tpeak methodology (see Chapter 7) is
commonly used to estimate T1/2keo that then links separate PK
and PD data sets. Tpeak will increase with age (see Fig. 8.3). Model
Tpeak Propofol = 1.14 × age + 2.08
6 R 2 = 0.27
5
4
3
2
1
0
0 2 4 6 8 10 12 14 16 18
B Age (years)
FIGURE 8.3  This figure shows the equilibration rate constant of propofol
and time to peak propofol concentration as a function of age. The keo decreases
with age; that is. the T1/2keo increases with age. This results in a later time
to peak concentration (Tpeak) as age (and weight) increases. (Data from
Jeleazcov C, Ihmsen H, Schmidt J, et al. Pharmacodynamic modelling of the
bispectral index response to propofol-based anesthesia during general surgery
in children. Br J Anaesth. 2008;100:509-516.)
dependence of the T1/2keo was demonstrated by an estimate of
1.7 min with the Kataria19 parameter set and 0.8 minute with the
Paedfusor model (Graseby Medical Ltd., Hertfordshire, UK)
parameter set.29
Pharmacodynamic Interaction Models
Drugs may interact with each other at multiple levels. These are
discussed in Chapters 6 and 7. Drug interactions for those drugs
used in TIVA are commonly described using PD interaction models.
TRADITIONAL METHODS
Traditional methods of evaluating PD interactions include using
isoboles (graphs illustrating equi-effective combinations of drugs),
shifts in dose (or concentration) response curves (see Chapter 7),
or interaction indexes based on parameters of potency derived
from separate monotherapy and combination therapy analyses.
Such methods provide an estimation of the magnitude of effect
for dose or concentration combinations, but they do not inform
us on the time course of that effect or its associated variability.
Competitive antagonists reduce receptor availability by compet-
ing for occupancy at the same receptor site. Drugs that elicit an
effect are called agonists, whereas those that do not are called
antagonists, so the occupancy of some receptors by the antagonists
results in less effect. In general, competitive antagonists shift the
effect-concentration curve to the right by altering the EC50. Non-
competitive antagonists shift the observed maximum effect (Emax)
rather than the EC50.
 Total Intravenous Anesthesia and Target-Controlled Infusion 181

Plasma neonate
7
Plasma child
Effect compartment T1/2 keo 0.5 min

8
6
Effect compartment T1/2 keo 1 min
Effect compartment T1/2 keo 2 min

Concentration (mg/L)
5
Effect compartment T1/2 keo 3 min
4

0
0 5 10 15
Time (minutes)

FIGURE 8.4  This figure shows simulated plasma time-concentration profiles for a typical 20-kg child given propofol
3 mg/kg using the Kataria parameter set. The T1/2keo used will affect predicted effect-site concentrations—that is,
the greater the T1/2keo, the longer it takes to achieve the target concentration.

100
Concentration of drug B
Reduced EC50
Effect (%)

for drug D*
A with drug B
A* B*
Drug A plus B
Drug A alone C*
0
A Concentration of drug A B Concentration of drug A
Effect (%)

Effect (%)

C*
B*
A*

Drug gB gB
A Dru Drug
A Dru
C D

FIGURE 8.5  Methods of investigating interactions. A, Shift in response curve analyses involve plotting the concentration
(or dose)-effect relationship for one drug alone and in the presence of steady-state concentrations of a second drug.
B, Isoboles are constructed using iso-effect lines with curves derived from observations assessed against the expected
(or “additive”) response line (B*). Supra-additivity is depicted by curves bowing toward the plot origin (C*), while
infra-additivity is shown with outward curves (D*). Information from both methods is represented within response
surfaces with isoboles displayed as horizontal planes and individual concentration-response curves as vertical slices
(indicated by arrows on surfaces for A* single concentration-response curve drug A, B* additive isobole, and C*
supra-additive isobole). C shows the additive response surface for two drugs. D shows the synergistic response
surface for two drugs, with synergy depicted through outward bowing of the surface. (Data from Hannam JA,
Anderson BJ. Pharmacodynamic interaction models in pediatric anesthesia. Pediatr Anesth. 2015;25:970–980.)

RESPONSE SURFACE MODELS
Emax models for individual drugs can be combined and extended
to incorporate PD interactions between two or more drugs.
The “response surface” models are an extension of empirical,
single-drug models that can be used to describe and predict the
combined effects between two or more drugs (Fig. 8.5). Horizontal
lines within the response surface hold equivalent information
to that given by isoboles. Surface parameters are estimated
using data points pertaining to all areas of the concentration
and effect range for both drugs simultaneously (as opposed to
considering individual concentration pairs or effect levels in
isolation, as is done with isobolographic analyses). Resulting
182 A Practice of Anesthesia for Infants and Children
PD models can be used to characterize the type of interaction
across the entire range of concentrations and responses and make
predictions about response (effect) for any ratio of the studied
drugs.59
Two equations are commonly used: those of Greco et al.60
and Minto and Vuyk61 (see Chapter 7). The Greco equations have
been used to describe additive effects for propofol, remifentanil,
and fentanyl on BIS response in children aged 1 to 16 years
undergoing general surgery.44 These authors reported EC50 estimates
of propofol 5.20 µg/mL, remifentanil 24.1 ng/mL, and fentanyl
8.6 ng/mL, and suggested a propofol and remifentanil pair of
2.3 µg/mL and 4.3 ng/mL, respectively, to maintain hemodynamic
parameters and sedation scores within ranges suitable for surgery.
The Greco model has also been used to describe loss of response
to various noxious stimuli under propofol-remifentanil anesthesia.62
Synergistic surfaces for sedation and response to laryngoscopy
were reported.
The Minto equations have been used to assess synergy for
hypnosis among three commonly combined drugs for anesthesia:
propofol, midazolam, and alfentanil.63 Computer simulations
based on interactions at the effect site predicted that a synergistic
three-drug combination (midazolam, propofol, and alfentanil)
tripled the duration of effect compared with propofol alone.
Response surfaces can describe anesthetic interactions, even those
among agonists, partial agonists, competitive antagonists, and
inverse agonists.63
Synergism between propofol and alfentanil has been demon-
strated using response-surface methodology. Remifentanil alone
had no appreciable effect on response to shaking and shouting
or response to laryngoscopy, whereas propofol could ablate both
responses. Modest remifentanil plasma concentrations dramatically
reduced the concentrations of propofol required to ablate both
responses.64 When comparing the different combinations of
midazolam, propofol, and alfentanil, the responses varied markedly
at each endpoint assessed and could not be predicted from the
responses of the individual agents.65 Similar response-surface
methodology has been used to investigate the combined administra-
tion of sevoflurane and alfentanil66 and remifentanil and propofol67
on control of ventilation. These combinations have a strikingly
synergistic effect on respiration, resulting in severe respiratory
depression in adults.
The ability of propofol to ablate responses to noxious stimuli
has been studied in children between 3 and 10 years undergoing
esophagogastroduodenoscopy.68 The EC50 for 50% probability of
no response was reduced from a propofol concentration of 3.7 µg/
mL to 2.8 µg/mL when it was combined with a remifentanil
infusion at 0.025 µg/kg per minute. Remifentanil infusions at
greater infusion rates did not further reduce the propofol require-
ments, but they did increase the risk of remifentanil-related adverse
respiratory events. The concurrent administration of opioids during
TIVA techniques in children has a significant “propofol-sparing”
effect while providing analgesia and stress control.68,69 It is sensible
to take advantage of this synergism to avoid excessive propofol
dosing and long-chain triglyceride loads, particularly with concerns
about PRIS during prolonged surgeries or sedations. Remifentanil
provides the most effective propofol-sparing effect, but fast recovery means
alternative techniques of analgesia must be well established before the
remifentanil is discontinued. Other analgesics and anesthetics are
also effective in reducing the propofol dose required. Fentanyl,
alfentanil, and sufentanil are effective, as are local and regional
analgesia techniques, once the block becomes established. Nitrous
oxide as well as low concentrations of inhalational anesthetics
also act synergistically with propofol and opioids to attenuate the
dose required.
Depth of Anesthesia Monitoring
A common effect measure used to assess depth of anesthesia is
the electroencephalogram (EEG) or a modification of detected
EEG signals (spectral edge frequency, BIS, entropy). Physiologic
studies in adults and children indicate that EEG-derived anesthesia
depth monitors can provide an imprecise and drug-dependent
measure of arousal. Although the outputs from these monitors
do not closely represent any true physiologic entity, they can be
used as guides for anesthesia and in so doing have improved
outcomes in adults. In older children the physiology, anatomy,
and clinical observations indicate the performance of the monitors
may be similar to that in adults. The BIS showed a close relationship
with the modeled effect-site propofol concentration and serves
as a measure of anesthetic drug effect in children older than 1
year.44 Their use in infants anesthetized with propofol cannot yet
be supported in theory or in practice.70,71 During anesthesia, the
EEG in infants is fundamentally different from the EEG in older
children; there remains a need for specific neonate-derived
algorithms if EEG-derived anesthesia depth monitors are to be
used in neonates.72,73
Depth of anesthesia monitors were used in 1% of all general
anesthetics in the United Kingdom in 2015. However, these moni-
tors were used in 33% of children undergoing general anesthesia
using a TIVA technique with a neuromuscular blocking drug, but
not at all in infants.74 Despite limitations in infants, BIS is useful
in older children, particularly when neuromuscular blocking drugs
are used in conjunction with TIVA; modified EEG has also been
successfully used for closed-loop anesthesia.16,20 These systems
may prove superior to open-loop systems that rely on a calculated
effect Ce that are associated with large variability.
Awareness has been more commonly reported after TIVA than
after gaseous anesthesia. However, many reports of awareness
occur after the switch from gaseous anesthesia to TIVA where a
loading dose was not given.75 Clearance of the gaseous anesthesia
agent occurs before attainment of effective steady-state propofol
concentrations. The future ability for point-of-care propofol assay
using either breath76,77 or plasma78–80 may be useful to reduce this
complication.
COMMON TIVA DRUGS
The commonly used medications include propofol, remifentanil,
alfentanil, and sufentanil; ketamine is occasionally used but has
a long context-sensitive half-time with consequent delayed awaken-
ing.81 Delivery can be achieved using either a manual infusion
scheme (Table 8.3) or PK model–driven infusion devices with
software developed specifically for use in children. Unfortunately,
the commercially available software packages usually limit the
applicable age to 1 to 3 years or older or weight to 10 to 15 kg
or greater, and the PK parameters are derived from studies of a
relatively few healthy children. Propofol programs that allow for
age-, weight- and gender-related changes in central compartment
volume, clearance, and distribution have been developed and
perform well in healthy children.82,83 However, there are consider-
able gaps in knowledge for some drugs, for ill children, and for
young children, infants, and neonates. Consequently, caution is
needed when applying such programs to these populations. The
anesthesiologist can use these preprogrammed devices as a basis
for initiating a TIVA technique but must also use skill, knowledge,
 Total Intravenous Anesthesia and Target-Controlled Infusion 183

TABLE 8.3 Manual Infusion Schemes

Drug Loading Dose Maintenance Infusion Notes
Propofol84 1 mg/kg 10 mg/kg per hour for 10 minutes,
then 8 mg/kg per hour for 10 minutes,
then 6 mg/kg per hour thereafter
Adult regimen to achieve blood concentration of
3 µg/mL
Underdelivers to children and achieves lower
8
blood concentration of 2 µg/mL
Propofol69 1 mg/kg 13 mg/kg per hour for 10 minutes, Concurrently with alfentanil infusion
then 11 mg/kg per hour for 10 minutes,
then 9 mg/kg per hour thereafter
Alfentanil85 10–50 µg/kg 1–5 µg/kg per minute Results in blood concentration of 50–200 ng/mL
Remifentanil86 0.5 µg/kg per minute for 3 minutes 0.25 µg/kg per minute Produces blood concentrations of 6–9 ng/mL
Remifentanil86 0.5–1.0 µg/kg over 1 minute 0.1–0.5 µg/kg per minute Produces blood concentrations of 5–10 ng/mL
Sufentanil86,87 0.1–0.5 µg/kg 0.005–0.01 µg/kg per minute Results in blood concentration of 0.2 ng/mL for
sedation and analgesia
Sufentanil86,87 1–5 µg/kg 0.01–0.05 µg/kg per minute Results in blood concentrations of 0.6–3.0 ng/
mL for anesthesia
Fentanyl85 1–10 µg/kg 0.1–0.2 µg/kg per minute
Ketamine85 1–2 mg/kg 0.1–2.5 mg/kg per hour Smaller dose and infusion rate for analgesia and
sedation. Larger dose and infusion rate for
anesthesia titrated to effect
Midazolam85 0.05–0.1 mg/kg 0.1–0.3 mg/kg per hour

5 Blood concentration
Concentration (µg/mL)

4 Effect-site concentration
Infusion rate in mL/hour
3
2
1

0
0 10 20 30 40 50 60 70 80 90 100 110 120
Time (minutes)

FIGURE 8.6  A fixed-rate infusion of propofol at 10 mg/kg per hour with no bolus dose in a healthy 10-kg, 1-year-old
infant. Note that a steady state is not reached even after 1 hour. There is a lag of effect-site concentration behind
blood concentration both during infusion and after stopping infusion. Effect-site concentration reaches blood
concentration at about 1 hour. The context-sensitive half-time is 9 minutes (simulated using Tivatrainer; available
at http://www.eurosiva.org/TivaTrainer/tivatrainer_main.htm).

and experience to titrate the IV agents to effect to avoid awareness,
pain, and adverse effects.
ACHIEVING THE TARGET CONCENTRATION IN A
MULTICOMPARTMENT MODEL
For a fixed infusion rate in a single-compartment model, it takes
five half-lives to reach a steady-state concentration (>96% of the
target) in the blood (Fig. 8.6). A loading dose is required to more
rapidly achieve the target concentration. This dose rapidly fills
the volume of distribution, after which the calculated infusion
maintains the blood concentration (Fig. 8.7). Calculation of the
loading dose is relatively easy for a simple one-compartment model.
Unfortunately, drugs such as propofol require two- or three-
compartment models to describe their disposition. A loading dose
may be too large if calculated using the volume of distribution
at steady state (Vss, where Vss = V1 + V2 + V3 for a three-
compartment model) for a drug that is described by multiple
compartments because it is initially administered into the smaller
central compartment (V1) to effect the desired response: loss of
consciousness. A loading dose based on the Vss will cause adverse
effects, hemodynamic instability, and/or toxicity. Even a remi-
fentanil bolus should be administered over several minutes to
reduce the risk of bradycardia, hypotension, and/or difficult mask
ventilation. An anticholinergic drug may prove useful if remifentanil
3 µg/kg is used for rapid-sequence intubation.
To more clearly understand the disposition of drugs after an
IV dose, it is useful to consider a three-compartment model (Fig.
8.8, Table 8.4). The drug is delivered and eliminated from a central
compartment V1 (which includes the blood) but also distributes
to and redistributes from two peripheral compartments, one
representing well-perfused organs and tissues (fast compartment,
V2) and the other representing more poorly perfused tissues such
as fat (slow compartment, V3). The transfer of the drug between
V1 and the two peripheral compartments (V2, V3), in addition
to the elimination of the drug from V1, is described by a series
of clearances (CL, Q2, Q3) indicating the distribution back and
forth between paired compartments, such as V1 to V2 and then
V2 back to V1. The primary target organ that intravenous anesthetic
agents affect is the brain. Therefore, an additional rate constant
is added to describe the equilibration between the central
184 A Practice of Anesthesia for Infants and Children

Concentration (Pg/mL)
Blood concentration
4 Effect-site concentration
Infusion rate in mL/hour
3
2
1

0
0 10 20 30 40 50 60 70 80 90 100 110 120
Time (minutes)

FIGURE 8.7  This figure illustrates the manual infusion technique in a healthy 70-kg 40-year-old. Note the importance
of the early higher initial infusion rates to ensure that the target concentration is more constant. (Data from the
Diprifusor pharmacokinetic data set.) Bolus dose (propofol 1%) was 1 mg/kg, then 10 mg/kg per hour for 10 minutes,
8 mg/kg per hour for 10 minutes, then 6 mg/kg per hour thereafter until 60 minutes when the infusion is discontinued.
The maximum blood concentration is 4.5 µg/mL. Effect-site concentration reaches 3 µg/mL after around 10 minutes
but drifts down to around 2.6 µg/mL and then very gradually rises. The context-sensitive half-time after 1-hour
infusion is 7 minutes.

Drug in

Q2 (L/min) Q3 (L/min)
Peripheral Central Peripheral
k21 (/min) k31 (/min)
V2 (L) V1 (L) V3 (L)
k12 (/min) k13 (/min)

k1e (min-1)
k10 (/min)
CL (L/min) Effect
Effect
compartment

keo (/min)

FIGURE 8.8  A three-compartment model with an additional compartment used to describe concentration in the
effect compartment. A single first-order parameter (k1e = keo at steady state) describes the equilibration rate between
the central (V1) and effect compartment. This compartment model is conceptualized in Fig. 8.9, where hydraulics
are used to illustrate compartment interactions. The arrows in this figure could be considered “pipes” that deliver
drug into the central compartment, out rapidly to V2 (and back to V1) and out more slowly to V3 (and back to V1)
and are then eliminated through simultaneous clearance. k1e is the rate constant describing drug movement from
compartment 1 to the effect compartment.

compartment and the effect site in the brain (keo = k1e at
equilibrium). This compartment is not represented by a volume
but rather by the time required to equilibrate. Consequently,
there is a time lag before changes in the blood concentration are
reflected in the effect site (shown on Figs. 8.6 and 8.7).
A hydraulic model is useful for understanding these concepts.
The central compartment is connected to the peripheral compart-
ments and effect site by a series of pipes of different diameters
and also a drainage pipe to represent elimination (Fig. 8.9A-F).
The height of the columns of fluid, which represents the concentra-
tion of drug, illustrates the gradient down which the drug travels
between the central and peripheral compartments; this can be
animated over time to show filling and emptying of compartments
relative to each other. The diameter of the interconnecting pipes
between the central and peripheral compartments represents the
intercompartment clearances (Q2, Q3), and the size of the drainage
channel represents elimination (CL). This hydraulic analogy is
used in the TIVA Trainer simulation program.88
Fixed Infusion Rate and a Three-Compartment Model
When a fixed infusion rate is started (see Fig. 8.6), the blood
concentration will increase but, almost simultaneously, distribu-
tion of the drug to the fast compartment and elimination both
begin. Distribution of drugs throughout the body contributes more
to the removal of drug from blood than elimination for most
medications. Remifentanil is an exception; it has extremely rapid
esterase clearance and elimination of this drug is far greater than
redistribution from the central compartment. As the concentra-
tions within each compartment equilibrate, the concentration
gradient between compartments lessens (slowing drug transfer
between compartments) but distribution to the slow compartment
continues along with elimination. The net effect is that the blood
 Total Intravenous Anesthesia and Target-Controlled Infusion 185

concentration continues to increase, albeit at a slower rate. As the a specific target concentration without overshoot. Then the rate
blood concentration increases toward equilibrium, elimination of infusion should decrease in a stepwise manner to maintain a
becomes relatively more important; Fig. 8.6 illustrates how far constant effect-site concentration until a steady state is reached.
behind the effect-site concentration lags. Eventually, after several
hours (or in some cases, days), a steady state is reached where the
infusion rate is directly proportional to clearance.
As drug is delivered into the central compartment, it continu-
ously distributes to the peripheral compartments while it is also
continuously eliminated. The infusion rate must vary because
8
it has to match the concurrent changes in the contribution of
Bolus and Variable Rate Infusion in a distribution and elimination with time (Figs. 8.10 and 8.11). When
Three-Compartment Model the infusion is stopped, then elimination will continue to drain
A loading dose can start to fill the central compartment and the central compartment, and drug will continue to distribute to
ideally should attempt to create an effect-site concentration at V2 and V3 along concentration gradients from V1 for some time.
Equilibrium may be reached, but the drug now begins to move back
from the peripheral compartments into the central compartment,
TABLE 8.4 Nomenclature for TCI Systems maintaining the central compartment drug concentration. This
can continue for a protracted interval, particularly for highly
Term Meaning Units lipid-soluble drugs that have a very large slow compartment V3
TCI Target-controlled infusion contributing a reservoir or depot effect (e.g., fentanyl; see Fig. 8.9F).
Vc or V1 Central compartment volume L Eventually the central compartment concentration will decrease.
V2 Fast compartment volume (vessel-rich L For most anesthetics, the longer the duration of an infusion, the
group) = V1 × k12/k21 more the drug has distributed into the peripheral compartments
V3 Slow compartment volume (vessel-poor L and the larger the reservoir of drug to be redistributed back into
group) = V3 × k13/k31 the central compartment and eliminated once the infusion ceases.
Cl 1 or CL Elimination clearance = V1 × k10 L/hour The half-time of the decrease in drug concentration in blood is
Cl 2 or Q2 Clearance between V1 and V2 = V2 × k21 L/hour related to the duration of the infusion for most drugs (except
Cl 3 or Q3 Clearance between V1 and V3 = V3 × k31 L/hour
remifentanil). This is termed the context-sensitive half-time (CSHT),
where the context is the duration of the infusion and relates to a
Cp Blood concentration
pseudo-steady state maintained by a TCI. For an individual drug in
Ce Effect-site concentration
an individual patient, CSHTs can be plotted against the duration
T Target concentration of the infusion (Fig. 8.12A and B). The CSHT will eventually
CALC Concentration calculated by TCI software asymptote and this is when the pseudo-steady state becomes a
MEAS Concentration measured true steady state. At that time, the infusion has become context
k10 Elimination rate constant /minute insensitive. This pattern is observed for nearly all IV anesthetics.
keo Rate constant for equilibration between /minute In the case of propofol, the slope of the context-sensitive half-life
blood and effect-site with time increases from adults to children to infants to full-term
T1/2keo Half-time for equilibration between blood minutes and then preterm neonates, with preterm neonates having the
and effect site greatest half-life of all age groups. The exception is remifentanil,
T1 2keo = LN (2) whose half-time becomes context insensitive almost immediately
keo
after initiation of the infusion because its elimination is rapid and
k12, k21 Rate constants for movement between V1 /minute
complete; the capacity of the red cell, plasma, and tissue esterase
and V2
enzyme systems are enormous.
k13, k31 Rate constants for movement between V1 /minute
PK parameters for remifentanil, alfentanil, and sufentanil are
and V3
summarized in Table 8.5.86 The differences in context-sensitive

TABLE 8.5 Pharmacokinetic Parameters for Short-Acting Opioids

Remifentanil34,89,90 Alfentanil91 Sufentanil92
V1 5.1–0.0201 × (age − 40) + 0.072 × (LBM − 55) Male: 0.111 × weight 0.164 × weight
Female: 1.15 × 0.111 × weight
V2 9.82–0.0811 × (age − 40) + 0.108 × (LBM − 55) 12.0 0.359 × weight
V3 5.42 10.5 1.263 × weight
k10 2.6–0.0162 × (age − 40) + 0.0191 × (LBM − 55)/V1 0.356/V1 0.089
k12 2.05–0.0301 × (age − 40)/V1 0.104 0.35
k21 2.05–0.0301 × (age − 40)/V2 0.067 0.16
k13 0.076–0.00113 × (age − 40)/V1 0.017 0.077
k31 0.076–0.00113 × (age − 40)/5.42 0.0126 0.01
keo 0.595–0.007 × (age − 40) 0.77 0.12

Age in years; weight in kilograms.

LBM, lean body mass.
From Absalom AR, Struys MMRF. An Overview of TCI and TIVA. Ghent, Belgium: Academia Press; 2005.
186 A Practice of Anesthesia for Infants and Children

10 200
Blood concentration
9 Effect-site concentration
Target concentration
8 Infusion rate in mL/hour

Infusion rate (mL/hour)

Concentration (Pg/mL)

5 100

3
50
2
25
1

0 0
0 10 20 30 40 50 60 70 80 90 100 110 120
Compartment concentration
Time (minutes) of propofol
Effect-site compartment
A concentration of propofol

10 200
Blood concentration
9 Effect-site concentration
Target concentration
8 Infusion rate in mL/hour

7 Infusion rate (mL/hour)

Concentration (Pg/mL)

5 100

3
50
2
25
1

0 0
0 10 20 30 40 50 60 70 80 90 100 110 120
Compartment concentration
Time (minutes) of propofol
Effect-site compartment
B concentration of propofol

FIGURE 8.9  A, Hydraulic model representation of effect-site TCI. Compartment volumes and intercompartmental
clearance values for the Paedfusor model in a healthy 10-kg, 1-year-old infant. In the first few minutes the central
compartment to effect-site concentration gradient is marked to “overpressure” the transfer of propofol to the effect
site. The peak blood concentration is 7.1 µg/mL. Distribution from the central compartment (C1) to the first peripheral
compartment (C2) occurs rapidly also, which slows the rise in effect-site concentration and blood concentration.
Elimination from C1 and distribution from C1 to the second peripheral compartment (C3) is also occurring. B, At
4.5 minutes, the effect-site concentration has reached the target of 3 µg/mL and has equilibrated with the concentration
in C1. The infusion device, which has been off after the initial loading infusion, now switches back on to maintain
the effect-site target concentration at 3 µg/mL.
 Total Intravenous Anesthesia and Target-Controlled Infusion 187

10 200
Blood concentration
9 Effect-site concentration

8
Target concentration
8 Infusion rate in mL/hour

7
Concentration (Pg/mL)

Infusion rate (mL/hour)

6

5 100

3
50
2
25
1

0 0
0 10 20 30 40 50 60 70 80 90 100 110 120
Compartment concentration
Time (minutes) of propofol
Effect-site compartment
C concentration of propofol

10 200
Blood concentration
9 Effect-site concentration
Target concentration
8 Infusion rate in mL/hour

7
Infusion rate (mL/hour)
Concentration (Pg/mL)

5 100

3
50
2 1.8 Pg/mL
1.5 Pg/mL 25
1

0 0
0 10 20 30 40 50 60 70 80 90 100 110 120
Compartment concentration
Time (minutes) of propofol
Effect-site compartment
D concentration of propofol

FIGURE 8.9, cont’d  C, After 1 hour of maintenance at an effect-site concentration of 3 µg/mL, the target is set to
0 µg/mL and the pump switches off. A total of 14 mL of propofol (1%) has been administered, or 14 mg/kg. There
is now a considerable accumulation of propofol in C2 and C3, while C1 and the effect site are still in equilibrium.
D, Approximately 10 minutes after the effect-site target concentration is set to 0, the blood concentration has halved;
thus the context-sensitive half-time is 10 minutes. The lag in the decline in effect-site concentration is clearly seen,
and there is now a gradient between effect site and C1. There is now also a concentration gradient from C2 to C1
and to C3 and this slows the decline in the concentration in C1. Continued
188 A Practice of Anesthesia for Infants and Children

10 200
Blood concentration
9 Effect-site concentration
Target concentration
8 Infusion rate in mL/hour

7
Concentration (Pg/mL)

Infusion rate (mL/hour)

6

5 100

3
50
2
25
1
0.6 Pg/mL
0 0
0 10 20 30 40 50 60 70 80 90 100 110 120
Compartment concentration
Time (minutes) of propofol
Effect-site compartment
E concentration of propofol

5 100
Blood concentration
Effect-site concentration
4 Target concentration
Infusion rate in mL/hour

Infusion rate (mL/hour)

Concentration (Pg/mL)

3
50
2

25
1
0.2 Pg/mL
0 0
0 10 20 30 40 50 60 70 80 90 100 110 120130 140 150 160 170 180 190 200210 220 230 240
Compartment concentration
Time (minutes) of propofol
Effect-site compartment
F concentration of propofol

FIGURE 8.9, cont’d  E, One hour after the infusion is stopped, the blood and effect-site concentrations have fallen
to 1 5 of the maintenance effect-site concentration. There are still considerable quantities of propofol in compartments
C2 and C3 that slow the decline of the concentration of C1 and effect-site concentrations. F, Even after 4 hours, the
depot of propofol in C2 and C3 is considerable, although blood and effect-site concentrations are extremely low.
However, these low concentrations may still be exerting significant antiemetic and anxiolytic effects (data from
the Paedfusor pharmacokinetic data set).
 Total Intravenous Anesthesia and Target-Controlled Infusion 189

Concentration (Pg/mL)
Blood concentration
4 Effect-site concentration

8
3 Infusion rate in mL/hour

2
1

0
0 10 20 30 40 50 60 70 80 90 100 110 120
Time (minutes)

FIGURE 8.10  This figure illustrates the manual infusion technique of propofol in a healthy 1-year-old, 10-kg child.
Note the importance of the early higher initial infusion rates to ensure that the target concentration is more constant.
The adult dose regimen is illustrated. The figure shows a bolus dose of 1 mg/kg, then 10 mg/kg per hour for 10
minutes, then 8 mg/kg per hour for 10 minutes, then 6 mg/kg per hour thereafter. The infusion was stopped at
60 minutes. The effect-site concentration dose does not equilibrate until 11 minutes. The blood and effect-site
concentrations stabilize around 1.8 µg/mL. However, this is unlikely to represent a sufficient depth of anesthesia
for surgery. The context-sensitive half-time after 1 hour infusion is 9 minutes (data from the Paedfusor pharmacokinetic
data set).

5
Concentration (Pg/mL)

Blood concentration
4 Effect-site concentration
3 Infusion rate in mL/hour

2
1

0
0 10 20 30 40 50 60 70 80 90 100 110 120
Time (minutes)

FIGURE 8.11  Manual infusion of propofol in 1-year-old, 10-kg child. The figure shows a bolus dose of 1 mg/kg,
then 13 mg/kg per hour for 10 minutes, then 11 mg/kg per hour for 10 minutes, then 9 mg/kg per hour thereafter.
The infusion was stopped at 60 minutes. The effect-site concentration does not equilibrate until 20 minutes. The
blood and effect-site concentrations stabilize around 2.4 µg/mL but gradually rise over the next hour to 2.6 µg/
mL. This concentration is larger than that achieved using the adult 10-8-6 regimen but may still be inadequate.
Larger infusion doses are required in a 1-year-old child. (Data from the Paedfusor pharmacokinetic data set.)

half-times are illustrated in Table 8.6 and Fig. 8.12A and B. Fentanyl TABLE 8.6 Context-Sensitive Half-Times (minutes) of Opioids
has a small CSHF when given by infusion for a short time, but in Children
this dramatically increases as the duration of the infusion increases.
Alfentanil’s CSHF reaches a plateau after approximately 90 minutes. Infusion Duration (minutes)
Opioid 10 100 200 300 600
THE TARGET-CONTROLLED INFUSION Remifentanil 3–6 3–6 3–6 3–6 3–6
A TCI is accomplished by a computer that performs rapid sequen- Alfentanil 10 45 55 58 60
tial calculations every 8 to 10 seconds to estimate the infusion
Sufentanil 20 25 35 60
rate required to produce a user-defined drug concentration in the
Fentanyl 12 30 100 200
blood or at the effect site of action of the drug in the brain in
an open-loop system.86 Thus TCI may be blood targeted or effect-site
targeted. The standard nomenclature for TCI systems is listed in
Table 8.4. Modern TCI systems are computer-controlled syringe children; neonatal and infant models are quite rare. Experience
drivers capable of infusion rates up to 1200 mL/hour with a with the various models may be gained by running the simula-
precision of 0.1 mL/hour. They incorporate a user interface and tion programs such as Tivatrainer (http://eurosiva.org/; European
display a range of safety alarms, monitoring functions, and warning Society for Intravenous Anaesthesia [EuroSIVA; Amsterdam, The
systems. For most programs, the user has to choose a drug and Netherlands) or Rugloop (http://www.demed.be/rugloop.htm;
its concentration from a menu and also select a PK parameter set Demed, Temse, Belgium) on a personal computer. Tivatrainer
(referred to as a model). The models suitable for use in children are now allows uploading of new models via a central website and
quite limited, and some models are not suitable for all age groups. server and contains details and simulations of pediatric models
Others may be suitable but have not been validated in younger for propofol and neonatal and pediatric models for sufentanil, in
190 A Practice of Anesthesia for Infants and Children

CSHT (short-duration infusions) TABLE 8.7 Paedfusor Propofol Pharmacokinetic Parameters

60 1–12 years V1 = 0.4584 × weight; V2 = V1 × k12/k21; V3 = V1 × k13/k31
Propofol
50 Fentanyl k10 = 0.1 527 × weight−0.3
x
Alfentanil x k12 = 0.114; k21 = 0.055
CSHT (minutes)

40 x Thiopentone x k13 = 0.0419; k31 = 0.0033

x keo = 0.26
30
13 years V1 = 0.400 × weight
x
20 k10 = 0.0678
(other constants as above)
10
14 years V1 = 0.342 × weight
x
0 x k10 = 0.0792
0 10 20 30 40 50 60 (other constants as above)
A Duration of infusion (minutes) 15 years V1 = 0.284 × weight
k10 = 0.0954
(other constants as above)
CSHT (long-duration infusions)
16 years V1 = 0.22857 × weight
600
Propofol k10 = 0.119
500 Fentanyl x (other constants as above)
x
Alfentanil x x
CSHT (minutes)

k10, Elimination rate constant; k12 and k21, rate constants for movement between V1
400 x Thiopentone x
and V2; k13 and k31, rate constants for movement between V1 and V3; keo, effect
x
Midazolam site equilibration rate constant; V1, central compartment volume; V2, fast compartment
300 x
volume; V3, slow compartment volume.
x Note: The k10 value in the age group 1–12 years is a negative power function of
200 weight that reflects the increasing clearance values in younger children.
x
Data from Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven
100 x
x x infusion of propofol in children. Brit J Anaesth. 1991;67:41-48; Rigby-Jones AE, Nolan
JA, Priston MJ, et al. Pharmacokinetics of propofol infusions in critically ill neonates,
0 infants, and children in an intensive care unit. Anesthesiology 2002;97:1393-1400;
0 1 2 3 4 5 6 7 8 9 10 11 12 Murat I, Billard V, Vernois J, et al. Pharmacokinetics of propofol after a single dose
B in children aged 1-3 years with minor burns. Comparison of three data analysis
Duration of infusion (hours)
approaches. Anesthesiology 1996;84:526-532.

FIGURE 8.12  A, Context-sensitive half-times (CSHTs) after short-duration

infusions. B, CSHTs after longer-duration infusions. For very lipid soluble drugs
such as fentanyl and propofol, V3 is very large compared with V1. Intercom- TABLE 8.8 Comparison Between Paedfusor and Kataria
partmental clearance between V1 and V3 is given by the equation V1 χ k13 = Models for Propofol in Children
V3 χ k31, which implies that if V1 is much smaller than V3, rapid distribution
from V1 to V3 is associated with very slow redistribution from V3 to V1. This Paedfusor93,94,97,98 Kataria99
is indeed seen with propofol and fentanyl, which have a slow offset of effects V1 0.458 × weight 0.41 × weight
after prolonged infusions. Propofol has a CSHT that varies between approxi- V2 0.95 × weight 0.78 × weight + 3.1 × age
mately 3 minutes for a short-duration infusion to approximately 18 minutes
V3 5.82 × weight 6.9 × weight
after a 12-hour infusion. This is because elimination is quite rapid compared
with the rate of redistribution from V3. For alfentanil, the concentration of k10 0.1 527 × weight–03 0.085
the un-ionized form is 100 times greater than that of fentanyl (pKa alfentanil k12 0.114 0.188
6.4, fentanyl 8.5). Alfentanil therefore has a more rapid onset time and shorter k21 0.055 0.102
half-life keo, a smaller V1, lower volume of distribution at steady state, and k13 0.0419 0.063
lower clearance than fentanyl. Fentanyl does, however, have a shorter CSHT
k31 0.0033 0.0038
than alfentanil after a short-duration infusion lasting less than 2 hours (A);
but for longer-duration infusions, alfentanil reaches a maximum CSHT after keo 0.26a N/Aa
about 90 minutes, whereas for fentanyl the CSHT continues to increase after a
This is the value for adults, but Munoz et al.101 have studied these two models to
12 hours (B). This is because fentanyl has a huge V3, and redistribution back define a more accurate keo for children age 3–11 years, and the values are 0.91 for
to V1 maintains the blood concentration when the infusion stops. (Simulated the Paedfusor model and 0.41 for the Kataria model. Jeleazcov et al.102 have derived
using Tivatrainer; available at www.eurosiva.org/TivaTrainer_main.htm.) age-related keo values by the formula keo = 1.03 × e−0.12 × age.

addition to a wide range of adult models for propofol, alfentanil,
remifentanil, fentanyl, ketamine, and midazolam. The simulation
shows animated graphs of blood and effect-site concentrations
against time, infusion rates, volumes, compartment sizes, and
many other features.
The models within TCI systems are derived from studies of
small numbers of healthy patients and are only a guide to drug
administration for an individual patient.83 The accuracy of TCI
propofol has been assessed in children.83,93 TCI propofol has
been incorporated into a modified version of the commercial
Diprifusor device and is known as the Paedfusor,94 which has
been evaluated clinically and performs well (Table 8.7).93,95,96
In children undergoing cardiac surgery, the model performed
significantly better than the adult model in adults.94,97,98 Parameter
estimates for the Kataria model are similar (Table 8.8) and it also
performs reasonably well,83,99 but all models have shortcomings.100
Experience shows that clinicians need to learn how to use each
model to optimize levels of anesthesia, ensure stability during
 Total Intravenous Anesthesia and Target-Controlled Infusion 191

10 200
Blood concentration
9 Effect-site concentration

8
Target concentration
8 Infusion rate in mL/hour

Infusion rate (mL/hour)

Concentration (µg/mL)

6
100
5

3
50
2
25
1

0 0
0 10 20 30 40 50 60 70 80 90 100 110 120
Time (minutes)

FIGURE 8.13  Target-controlled infusion modeled using the Paedfusor pharmacokinetic data set. Effect-site–targeted
infusion of propofol in a healthy 1-year-old, 10-kg child. The effect-site target is 3 µg/mL. The figure shows a bolus
dose of 3.4 mg/kg delivered at 45.5 mL/hour to accentuate the gradient from blood to effect site, then the infusion
switches off for 4 minutes. Peak blood concentration after bolus dose is 7.1 µg/mL. Stepwise-reducing the infusion
from 15.7 mg/kg per hour to 9.5 mg/kg per hour for 1 hour was done. The infusion was stopped at 60 minutes
(i.e., effect-site target is set for 0 µg/mL). The effect-site concentration reaches 3 µg/mL at 3 minutes 39 seconds.
The total dose of propofol is 14 mg/kg. The context-sensitive half-time is 10 minutes 37 seconds.

induction and maintenance phases, and enhance recovery speed TABLE 8.9 Example of Target-Controlled Infusion (Propofol
and quality. Most pediatric models overestimate the initial volume 5 µg/mL) Based on Calculated Blood-
of distribution, which risks too large an initial bolus dose.83 The Concentration Targeting Compared With
Paedfusor model makes an allowance for the increased clearance Calculated Effect-Site Concentration Targeting for
with age (per kilogram) in younger children; particularly those a Healthy 1-Year-Old (10 kg), Using the Paedfusor
below 30 kg in weight (see Tables 8.7 and 8.8, Fig. 8.13). The Pharmacokinetic Data Set
minimum age and weight limits for each model also differ with
age 1 year and 5 kg for the Paedfusor system and 3 years and Effect-Site
15 kg for the Kataria system. Below a weight 12.5 kg and age 2 Blood Concentration Concentration
Targeting Targeting
years, the second compartment becomes negative with the Kataria
model, which means that model cannot be used clinically in Loading dose 1.7 mg/kg 5.7 mg/kga
such young patients. For simulation using the Paedfusor data set, Maximum blood target 5 µg/kg 12 µg/kga
the adult value for keo of 0.26/minute (T1/2keo 2.7 minutes) can reached
be used (see Table 8.8). This means effect-site targeting may be Total propofol infused 23.2 mg/kg 23.3 mg/kg
simulated with the Paedfusor model (Table 8.9), and it may be after 60 minutes
possible to display an effect-site predicted concentration while Time to achieve effect 17.5 minutes 4.5 minutesb
using a pump in blood-targeted TCI mode, as with Diprifusor. site target of 5 µg/mL
Attempts have been made to define a more accurate keo for a
Potential for hemodynamic changes due to high peak blood concentration from
children in an ingenious study using auditory evoked responses larger bolus dose.
with both the Paedfusor and Kataria models.101 For children age 3 b
Very much shorter time to achieve effect-site target.
to 11 years, the median extrapolated keo values for the Paedfusor
models was 0.91/minute (T1/2keo 0.8 minutes) and for the Kataria
model 0.41/minute (T1/2keo 1.7 minutes). The BIS was used to not interchangeable.83,100 It can be argued that these calculations
derive a value for the time to peak effect, and hence, keo.87,102,103 and extrapolations are a trick to sidestep imperfect PK values.83,100
It was concluded that the time to peak effect after a bolus dose Integrating pharmacokinetic and pharmacodynamics into models
was shorter in children than adults as the extrapolated T1/2keo appropriate for use in children is challenging, not the least because
values were considerably smaller.100 Similar findings were reported of doubts about the sensitivity and specificity of the depth of
by Hahn et al. using state entropy monitoring.104 This approach anesthesia monitoring in children.33,104–106
has enabled calculation of an age-specific range of values for the Some pumps display predicted plasma or effect site concentra-
keo (see Fig. 8.3), which should allow more accurate effect-site tions from the programmed PK model and are invaluable as an
targeting using propofol in the future. It must be stressed that educational tool for demonstrating the intricacies of TIVA. TCI
compartmental values are highly specific to a single model and are pumps do not have current FDA approval within North America,
192 A Practice of Anesthesia for Infants and Children
Propofol CSHT by model
(effect site target 3 µg/mL)
40
35 “Jeleazcov model”
Kataria model
30 Paedfusor model
CSHT (minutes)
25
20
15
10
5
0 1
15 30 60 120 240 360 480
Infusion duration (minutes)
FIGURE 8.14  The predicted context-sensitive half-time (CSHT) of propofol
depends on the pharmacokinetic model. Effect-site targeting can result in
higher propofol doses if the keo is incorrect. The Jeleazcov model uses
age-appropriate keo values and this results in the shortest predicted CSHTs
for all infusion durations. This has clinical importance as it predicts a shorter
recovery time for a given target concentration. (Data from Limb J, Morton NS.
Age specific effect-site TCI in children; modelling using Tivatrainer. Anaesthesia
2010;65:542; and Absalom A, Vereecke HE, Eleveld DJ. A hitch-hiker’s guide
to the intravenous PK/PD galaxy. Paediatr Anaesth. 2011;21:915-918.)
but it is anticipated that approval will be granted in the near
future.
Effect-site targeting offers the advantages of more rapid achieve-
ment of desired depth of anesthesia and less titration of the
target depth in practice, but while it has been used in research in
children, it has yet to become a clinical tool.107 Table 8.9 shows
how the behavior of the TCI infusion differs between blood and
effect-site targeted infusion using the adult keo of 0.26/minute
(T1/2keo 2.7 minutes). It can be expected that effect-site targeting
may have more profound cardiovascular and respiratory effects
than blood targeting owing to the larger initial bolus doses with
resultant higher peak blood propofol concentrations attained.107 It is
known that slower administration of propofol preserves spontaneous
respiration in children,108 and the use of an age-appropriate T1/2keo
value and careful titration from a low initial target value may
ameliorate some adverse effects. Without such titration, adverse
effects may be more marked in infants (Fig. 8.14).102,107 Although
the use of BIS remains uncertain in children,109 particularly those
younger than age 1 year, the use of age- or weight-appropriate
T1/2keo values in TCI systems provides the prospect of more
accurate and efficient propofol delivery to children.107 This has
safety implications in terms of reducing lipid load and clinical
utility by increasing speed of recovery (Fig. 8.15).
A Practical Approach in Children
Mastery of TIVA requires familiarity with the technique. Such
familiarity can be gained by practice with older children before
progressing to those younger and beginning with children who
present for elective, nonurgent surgery where a known stimulus
will be applied. Cooperation from surgical colleagues is always
advantageous when mastering the use of TIVA.
14
12
10
Propofol (µg/mL)
8
6
4
2
0
2 3 4 5 6 7 8 9 10
Age (years)
Paedfusor Jeleazcov Munoz (PF) Munoz (Kat)
FIGURE 8.15  The peak plasma concentrations attained in simulations in Fig.
8.14 for an effect-site target of 5 µg/mL are shown. A large bolus dose does
not necessarily equate to high peak plasma concentrations because of the
variable volumes of distribution in the pediatric models at different ages.
Even though more drug may be administered when using effect-site targeting
if the keo is inappropriate, this may not mean an increase in peak plasma
concentration because the peripheral volumes of distribution may be increased
in any one model. More drug is redistributed. (Data from Limb J, Morton NS.
Age specific effect-site TCI in children; modelling using Tivatrainer. Anaesthesia
2010;65:542; and Absalom A, Vereecke HE, Eleveld DJ. A hitch-hiker’s guide
to the intravenous PK/PD galaxy. Paediatr Anaesth. 2011;21:915-918.)
DRUG DELIVERY
Secure IV access is essential to safely administer TIVA. A dedicated
line is not necessarily required as long as there is access to the
IV cannula being used. Syringes that screw into infusion sets
reduce the risk of poor or leaky connections. Infusion lines should
be placed as close as possible to the venous cannula.110 The setup
should prevent retrograde infusion of propofol up the IV infusion
set if resistance to flow into the cannula is greater than that in
the fluid line. This is optimally achieved using one-way, nonreturn
valves to prevent backflow up the IV fluid line. Percutaneous
intravenous central catheters (PICC) may be unsatisfactory because
high infusion rates are not possible. Combined infusions into a
single vein run the risk of an inadvertent bolus of a companion
drug. Anesthesia for major surgery may be best served using central
venous access, diminishing the risk of unintended subcutaneous
infusion. The infusion site is not always readily accessible in small
children whose limbs may be covered in surgical drapes, and
inadvertent dislodgment, obstruction, or subcutaneous tissue
infiltration may occur. Common drug delivery problems are listed
in Table 8.10.
Although closed-loop anesthesia is currently impractical because
effect measures are poor in infants and neonates, changes in cerebral
effect measures with changes of dose may at least confirm that
the infusion is not disconnected or subcutaneous. Pump perfor-
mance characteristics (e.g., lag time), IV tubing dead space, and
syringe size and type all contribute to the observed response (see
also Chapter 52). The more dilute the solution, the faster the
syringe plunger travels with a better matched delivery to change
the drug delivery prescription.110 Dilution is especially important
 Total Intravenous Anesthesia and Target-Controlled Infusion 193

TABLE 8.10 Potential Problems With Drug Delivery From TABLE 8.11 Possible Weight-Based Propofol Regimes
Intravenous Anesthesia Pumpsa in Children
Problem
IV cannula disconnect/out of
vein
Prevention/Detection/Solution
Venous access should be visible
and accessible during procedure
Weight
>35 kg
15–35 kg
Infusion Scheme
Schneider effect-site concentration model
Kataria plasma concentration model or
8
Disconnection of infusion Pump and tubing connections McFarlan manual plasma concentration regimen
tubing from pump or cannula should be visible
<15 kg Steur manual infusion regimen
Use Luer-lock syringes
Pump power supply failure or Ensure pump has an audible alarm
pump paused prudent thing to do may be to convert to an inhalational anesthetic
Occlusion of IV cannula or Pump high-pressure alarm technique if clinically appropriate.
tubing
Occlusion alarm because of Ability to alter alarm threshold INFUSION REGIMES
small cannula or long infusion In general, the TCI pumps deliver propofol more accurately than
tubing (e.g., PICC) manual regimes, result in better hemodynamic stability, use a
“Backtracking” of propofol into Use of one-way valves lower induction dose, and result in improved recovery time. If a
intravenous fluid infusion dedicated TCI pump is available, then it should be preferred over
tubing a manual regime. Surgical anesthesia is generally obtained with
Drug disparity between settings Keep only one concentration of a propofol effect site concentration of 4 to 6 µg/mL. This will
and drug used (e.g., different propofol in hospital. Double-check be achieved more rapidly with an effect-site target model than
concentration) drug dilution concentrations (or with plasma-targeted models because of equilibration between
dispense from pharmacy premixed)
the plasma concentration and effect-site concentration.
A dedicated IV with a constant Most TCI programs (models) are inaccurate for some ages
carrier solution for TIVA is the ideal
within their specified age ranges28–30 or when parameter estimates
Wrong drug programmed into Prominent pump displays with the have not been tested (e.g., intensive care patients or children with
pump (remifentanil rather than drug name.
neuromuscular disease undergoing scoliosis surgery).80 Clearance
propofol) Color coding of the pump LCD (per kilogram) is increased as age decreases in children (allometric
displays and syringe labels
theory). The Kataria parameter set is known to underpredict
Bar coding concentration as age increases, consistent with allometric scaling.
a
Adapted from Nimmo AF, Cook TM. Accidental awareness during general anesthesia When this parameter set is used to estimate PD parameters, it
in the United Kingdom and Ireland. In: Pandit JJ, Cook TM, eds. National Audit appears that the older children require lower concentrations to
Project, ed 5. Royal College of Anaesthetists and the Association of Anaesthetists maintain anesthesia47; this is a PK effect and not a PD effect.48
of Great Britain and Ireland, 2014:151-158. PICC, percutaneous intravenous central
The adult Schnider112 model may be more accurate than either
catheters.
the pediatric Kataria,19 pediatric Marsh21 or Schuttler25 models in
children weighing more than 35 kg.33 The Schnider effect-site–
targeted model has also been shown to have better accuracy in
in improving the accuracy of delivery in infants and neonates. adults.113 The Kataria TCI model is plasma targeted and is valid
Modified EEG monitoring (e.g., BIS) is not necessary in the for children from 3 to 15 years weighing 15 to 65 kg. For children
spontaneously breathing patient but should be considered in the younger than 3 years, Steur et al.50 have produced a manual regime
patient who is receiving TIVA and neuromuscular blockade. The (see Table 8.2). Neonates are susceptible to hypotension with
BIS is reasonably valid for children as young as approximately 3 propofol51 and it is advisable to gradually increase infusion rate
years of age with propofol, but there are very limited data for until anesthesia is achieved rather than starting at a high infusion
other medications. It is essential to appreciate that in younger rate.114 Manual regimes have also been produced to mimic Kataria
children the BIS number may not be reliable, but some interpreta- plasma targeted infusion for 3 to 6 µg/mL.18,115 One approach to
tion can be made from BIS number changes rather than the the use of propofol regimes in children for TIVA is shown in
absolute BIS number displayed. Table 8.11.
TCI parameter sets (models) available for use in children
generate different plasma propofol concentrations. It is important The Obese Child
to be aware of these differences; this is especially so with regard Problems with drug dosing in obese adults are also common in
to the initial loading dose. Consequently, it is important to be children. The size metric varies with both drug and infusion type.
aware of the performance of the infusion pump being used, the The initial bolus may depend on the lean body mass, whereas the
particular parameter set installed, and its appropriateness for a infusion rate may depend on another size metric. For example,
given clinical scenario. The immature neonate, the critically ill propofol infusion rates relate best to total body weight scaled
child, or the child with major organ failure needs a smaller dose using allometry,45,116 whereas lean body weight is a better metric
of IV anesthetic agent; care is particularly needed in children for remifentanil infusions. A further complication is that the
receiving vasoactive medication and those with congenital heart calculator program117 of the pump used to estimate lean body
disease.111 Titration is advisable to allow for between-subject mass fails in short obese people.118 Solutions to this problem
variability of PK and PD parameters. include setting limits on maximum weight,119 inventing a fictitious
Pumps should be serviced regularly. Unrecognized pump failures height,120 or creating a new metric121; use of a better metric such
can occur with subsequent patient awareness or overdose so vigi- as fat-free mass might be the best solution.118 Investigations using
lance is required. If problems with anesthesia occur, then the normal fat mass122 as a size metric suggest that the appropriate
194 A Practice of Anesthesia for Infants and Children

“size” may differ for each drug. These dose calculation problems
can be circumvented by reducing the target concentration (e.g.,
propofol 4 µg/mL rather than 6 µg/mL) and then titrating to
effect. The use of a cerebral function monitor such as BIS can be
helpful.
target of 6 µg/mL requires ventilatory support. Although such
mixtures are widely used, remifentanil in such mixtures may become
unstable and has a limited life span in the syringe. The weaker
the mixture, the less stable it is. This is due to a pH effect on the
rate of ester hydrolysis of the remifentanil.128

Remifentanil as an Adjunct Injection Pain With Propofol

Remifentanil is very useful as an adjunct.123,124 It adds a degree of
“smoothing” even in those children who require sedation only
(e.g., radiologic imaging). Propofol is not an analgesic and the
addition of remifentanil reduces movement in response to surgical
stimulation125; there is approximately 30% more movement with
propofol compared with an inhalational anesthetic. Remifentanil
also reduces the propofol target concentration.67,126 The consequent
propofol dose reduction can be useful when anesthesia duration
is prolonged because the concomitant context-sensitive half-life
of propofol increases over time and concomitant remifentanil
adjunct allows earlier awakening. Remifentanil is also useful to
reduce pain during limb procedures where a tourniquet is used.
Most children will maintain spontaneous respirations with a
remifentanil-propofol combination. Fig. 7.26 demonstrates the
remifentanil infusion rates that will maintain a spontaneous respira-
tion rate of 10 breaths/minute. Use of the adult Minto parameter
set for remifentanil infusion in children confers a degree of safety
because concentrations measured will be lower than those predicted
because of the higher clearance (expressed as per kilogram) in
children. Occasionally some respiratory support may be required;
that is easily done using the pressure support ventilation mode.
Controlled ventilation is required when high target concentrations
of remifentanil are used. High effect-site remifentanil concentrations
(>10 ng/mL) are associated with hypotension (Fig. 8.16) and this
property can be used advantageously during some neurosurgical
procedures or spinal instrumentation.127
Fixed propofol-remifentanil combinations (mixed together in
the same syringe) are frowned upon by some because (1) they do
not allow separate titration of analgesia and sedation and (2) target-
ing a propofol concentration can result in a relatively large bolus
of remifentanil. However, they remain widely used—for example,
propofol 10 mg/mL with remifentanil 5 µg/mL. If a combination
is used with a TCI pump then a propofol target concentration
of 3 µg/L usually allows spontaneous breathing, whereas a propofol
The pain associated with IV injection of propofol is problematic.
This is especially common when given through the small veins
in the hands or feet. Perhaps the best approach to reduce injection
pain is to place a larger-bore cannula in a large vein. Lignocaine
1 mg/kg placed in the IV with a proximal tourniquet (or just
manual compression of the arm to stop the IV from flowing)
applied for 30 to 60 seconds effectively attenuates this pain. Opioid
or ketamine administered IV before propofol injection is also
helpful. This can be best done by beginning the remifentanil
infusion first and running it at a Cp of approximately 2 to 3 ng/
mL for 2 minutes (using the Minto model) before starting the
propofol infusion; most children and adults will continue to
maintain spontaneous respirations through this short period.
Alternatively, a bolus of fentanyl 1 µg/kg or remifentanil 1 µg/
kg through the IV cannula is effective.
ESTABLISHING TIVA AFTER AN INHALATIONAL INDUCTION
Inhalational induction is standard in many pediatric centers.
Propofol TIVA can start once gaseous induction has been performed
and IV access obtained. The use of a fixed infusion rate only is
frowned upon because steady-state concentrations will not be
established before 3 to 4 elimination half-lives (see Fig. 8.6). While
end-tidal inhalational agent partial pressure decreases, it is reason-
able to target a reduced propofol concentration of 3 µg/mL as
an initial target and then titrate against clinical response. If using
a manual regimen, then reduce the initial bolus, especially if
spontaneous respirations is required; a bolus of propofol 1 mg/
kg is usually satisfactory.
PRACTICAL APPROACHES FOR SOME CLINICAL SCENARIOS
Spontaneously Breathing Diagnostic Procedures
(Radiology Investigations)
Anesthesia and spontaneous respiration will generally be maintained
at a target of 4 to 6 µg/mL in the absence of opioids or other

80 MAP at high concentration uncertain

70

60
MAP (mmHg)

50 Little effect at
40 low concentrations

30

20

10 Target concentrations EC50

0
0 5 10 15 20 25
Effect compartment concentration (ng/ml)

FIGURE 8.16  The relationship between remifentanil concentration and mean arterial blood pressure (MAP) in infants
(4 months to 1 year) undergoing cranioplasty surgery. A steady-state remifentanil concentration of 14 µg/L would
typically achieve a 30% decrease in mean arterial blood pressure. EC50, concentration is that at half maximum
response. (From Anderson BJ, Holford NH. Leaving no stone unturned, or extracting blood from stone? Paediatr
Anaesth. 2010;20:1-6. Used with permission.)

adjuncts. Pressure-supported respirations using either an endotra-
cheal tube (ETT) or a laryngeal mask airway (LMA) will generally
maintain normal or near normal PaCO2. In the absence of pressure
support ventilation, PaCO2 will increase.
Spontaneously Breathing Airway Procedures Without an
Endotracheal Tube (Flexible Respiratory Bronchoscopy,
Rigid Laryngobronchoscopy)
Anesthesia may be induced by either inhalational or IV means.
If induction is inhalational, then an initial propofol target of
3 µg/mL is reasonable to maintain desired spontaneous respirations
and this target can then be titrated against response. If IV induction
is used, then a plasma target of 4 to 6 µg/mL is reasonable but
induction should be slow, especially if using an effect target model,
because the relatively larger propofol bolus used to rapidly obtain
the target Ce may cause apnea.
Remifentanil helps dampen airway reactivity and is a useful
adjuvant. A remifentanil bolus of 1 µg/kg followed by an infusion
at a low dose of 0.02 to 0.03 µg/kg per minute is effective. The
remifentanil infusion can then be titrated to maintain a normal
respiratory rate. If using the Minto Ce TCI model, then starting
at an initial target of 1 µg/mL can be titrated to effect.
Laryngoscopy and topicalization with lidocaine can be carried
out following induction. Generally laryngoscopy is tolerated
more quickly if inhalational induction has been performed
first. If using an IV induction, it pays to bide your time before
performing laryngoscopy and topicalization; this allows effect-site
equilibration.
Once the procedure has commenced, reactivity can be addressed
by slow increments of propofol (1 µg/mL Cp or Ce if using TCI
or 1 mg/kg bolus if using a manual regimen) and by increasing
the remifentanil infusion. Further topicalization may be useful.
It is generally best to avoid large boluses of propofol as this may
induce apnea.
Spontaneously Breathing Procedures With an Endotracheal
Tube (Adenotonsillectomy)
Induction may be either inhalational or IV. Intubation can be
performed once the desired Cp or Ce has been achieved or after
a bolus dose has been administered. The most stimulating part
of the procedure is often mouth gag (e.g., Boyle-Davis) place-
ment. Propofol can be increased in anticipation of this response
to gag stimulation. This may cause apnea but once surgery has
commenced, propofol can be slowly reduced until spontaneous
respirations return.
Spontaneously Breathing Surgical Procedures With an LMA
(Orthopedic and Peripheral Surgical Procedures)
Induction can be inhalational or an IV technique can be used.
Commence propofol with an appropriate bolus if using a manual
regimen. Remifentanil is a very useful adjunct, especially with
peripheral orthopedic procedures where regional local anesthesia
blockade has not been placed, to prevent movement in response
to surgical stimulation.
BIS monitoring is a useful adjunct to titrate the propofol dose.
Generally children will maintain spontaneous respirations with a
BIS score in the 40 to 60 range and a remifentanil infusion of 0.1
to 0.2 µg/kg per minute or an effect concentration of 3 µg/mL
Ce using the Minto model. Spontaneous respirations may not
be adequate to provide CO2 clearance and respiratory support
may be required. Remifentanil remains a useful agent even if
regional blockade has been used. It facilitates rapid induction
and ready performance of the block without response to needle
Total Intravenous Anesthesia and Target-Controlled Infusion 195
placement. Furthermore, it provides analgesia while the block
takes effect and reduces any response to tourniquet pain. With
the absence of surgical stimulation owing to a functional block,
the propofol dose can generally be reduced. The remifentanil
infusion or target concentration can also be reduced to assess block
function.
8
Remifentanil is not necessarily useful if central blockade is used.
However, it is still helpful for induction and during airway manage-
ment and block placement. Infusion rate or target concentration
can then be reduced or stopped once the block is established.
Major Invasive Procedures With Intubation (General,
Thoracic, Neurosurgical, or Major Orthopedic Surgery
(e.g., Posterior Spinal Fusion)
Commencement of TCI or a manual regimen can be followed by
neuromuscular blockade and airway management. Remifentanil
blunts the intubation response. Modified EEG monitoring in such
patients undergoing major surgery is prudent. This may be achieved
using the actual BIS score or the processed EEG waveform if the
patient is younger than 3 years of age. Remifentanil is useful to
reduce the total propofol dose and avoid delayed awakening at the
end of the procedure. Analgesia can be managed with multimodal
analgesia schemes and/or regional or neuraxial blockade.
Toward the later stages of the procedure, the propofol infusion
may be reduced by titration against the EEG. This allows for a
more rapid return of consciousness. One approach at the end of
the procedure is to reverse residual neuromuscular blockade and
stop both propofol and remifentanil infusions. Generally by the
time the remifentanil effect has worn off, spontaneous respirations
will have returned and anesthesia is still deep, attributable to
propofol’s prolonged CSHT; extubation can then proceed safely.
A Neonate Having Combined Anesthesia and
Regional Blockade
There are concerns that some anesthetic drugs may cause neuronal
apoptosis in the developing brain of a human neonate (see also
Chapter 25) because drugs that bind to γ-aminobutyric acid-A
(GABAA) receptors cause neuronal apoptosis and other neuro-
degenerative changes in animal models ranging from rodents to
primates.129 Dexmedetomidine130,131 and remifentanil130,131 may be
alternative options because their action is not mediated through
GABAA receptors and they do not cause neuronal apoptosis or other
neurodegenerative effects in rodents and primates. Dexmedetomi-
dine also attenuates isoflurane-induced neurocognitive impairment
in neonatal rats.132 One regimen consists of IV premedication of
glycopyrrolate 5 µg/kg followed by a dexmedetomidine 1-µg/kg
loading dose over 10 minutes and remifentanil 1 µg/kg over 1 to
2 minutes. The dexmedetomidine infusion 1 µg/kg per hour can
be started and titrated up or down within 50% of starting doses as
needed, although it is crucial to appreciate that dexmedetomidine is
not a complete general anesthetic. Similarly, a remifentanil infusion
0.1 µg/kg per minute can be titrated up or down (maximum
infusion 0.5 µg/kg per minute). Airway management may require
an ETT or LMA and ventilation assisted to maintain normocapnia.
COMMON MANUAL PROPOFOL INFUSION SCHEMES
Adults
A simple scheme was devised to maintain a blood concentration
of propofol in healthy adults of 3 µg/mL.133 A bolus IV dose of
1 mg/kg is followed by a continuous infusion of 10 mg/kg per hour
for 10 minutes, then 8 mg/kg per hour for 10 minutes, then 6 mg/
kg per hour (Fig. 8.17).133 When this “10-8-6” regimen is modeled
and verified using the Marsh model for an adult patient, the
196 A Practice of Anesthesia for Infants and Children

14

12

Concentration (µg/mL)
10
Adult
8 Child

0
0 10 20 30 40 50
Time (minutes)

FIGURE 8.17  Simulated time-concentration profiles for propofol using a pediatric parameters set and an adult set.
A 3 mg/kg bolus was administered and the infusions were administered as for an adult (10-8-6 regimen). Peak
concentrations in the child are lower because of an increased volume of distribution. Increased clearance (expressed
per kilogram) in children means subsequent concentrations also remain lower.

estimated blood concentration slightly exceeds 3 µg/mL but Lipid load (g/kg) at 480 minutes
remains reasonably stable.93 1.4

Adolescents 1.2 Blood target 3 µg/mL

Adolescents can generally be grouped as small adults and the
1
Lipid load (g/kg)

10-8-6 regimen can be used (see Table 8.3).133

0.8
Children
Children require larger infusion rates of propofol than adults to 0.6
maintain clinical anesthesia (Fig. 8.17) because clearance (expressed 0.4
per kilogram) is greater in children than in adults (Table 8.12).
Parameter estimates reported by Kataria19 were used to determine 0.2
infusion regimens that maintain a steady-state blood concentration 0
of 3 µg/mL in children aged 3 to 11 years. A loading dose of
5 10 20 30 70
2.5 mg/kg followed by an infusion rate of 15 mg/kg per hour for
the first 15 minutes, 13 mg/kg per hour from 15 to 30 minutes, Weight (kg)
11 mg/kg per hour from 30 to 60 minutes, 10 mg/kg per hour
FIGURE 8.18  Lipid load after 480 minutes of a blood targeted propofol
from 1 to 2 hours, and 9 mg/kg per hour from 2 to 4 hours was 1% infusion (formulated in vehicle containing 0.1 g/mL lipid) with target
proposed. The CSHT in children was greater than in adults, concentration of 3 µg/mL. Note the smaller infants have almost twice the
increasing from 10.4 minutes at 1 hour to 19.6 minutes at 4 hours lipid load and so 2% propofol is recommended to halve the relative lipid
compared with adult estimates of 6.7 minutes and 9.5 minutes, exposure and other propofol-sparing and lipid-sparing measures should be
respectively.18 Subsequent clinical assessment of the infusion used. (Simulated using Tivatrainer; available at http://www.eurosiva.org/
regimen’s performance proved acceptable.115 TivaTrainer/tivatrainer_main.htm.)
This increased dose requirement for propofol in children can
cause problems because it is formulated as a lipid emulsion and
the lipid load can be considerable, particularly in young infants
(Fig. 8.18). Propofol formulations are now available in some TABLE 8.12 Differences Between Adult and Pediatric Propofol
countries in concentrations varying from 5 mg/mL to 20 mg/mL Pharmacokinetic Parameters
(0.5%–2%); the most effective “lipid-sparing” strategy for infusions
Elimination Clearance
is to use 20 mg/mL propofol (2%) as this immediately halves the Age Vd (mL/kg) Half-Life (minutes) (mL/minute per kg)
lipid load.
1–3 years 9500 188 53
Infants 3–11 years 9700 398 34
With the clearance of propofol reduced in infants, one might Adult 4700 312 28
anticipate infusion rates at steady state reduced to similar extents. Notes: The apparent volume of distribution (Vd) of propofol in the child is twice
However, infusion rates for children younger than 3 years of age that of adults. The clearance of propofol in young children is twice that of adults
based on clinical experience from a pilot study of 50 patients and elimination is much more rapid.
Data from Absalom A, Struys MMRF. An Overview of TCI and TIVA. Gent, Belgium:
were actually increased. This experience was used to develop dose
Academia Press; 2005.
regimens that were then evaluated in 2271 children undergoing

anesthesia with mechanical ventilation. Infusion changes were
every 10 minutes, similar to that proposed by Roberts et al. in
adults.133 These are shown in Table 8.2. Few adverse effects were
recorded—(bradycardia (12%), blood pressure decrease (8%), oxygen
saturation decrease (1%)—all of which were easily countered by
routine measures.50
COMMON MANUAL OPIOID INFUSION SCHEMES
Simple manual infusion regimens can be used for the opioids
fentanyl, alfentanil, remifentanil, and sufentanil. The manual
infusion regimens for these opioids in children are summarized
in Table 8.3. Maintenance analgesia after infusions of these
opioids should be planned, and it is important that adequate
doses of systemic analgesics are given well before the infusion is
discontinued. Transitioning is somewhat smoother after sufentanil
than after alfentanil or remifentanil in children. The problem
of acute tolerance to ultra-short-acting opioids (see Chapter 7)
has been noted after use of remifentanil in surgery for pediatric
scoliosis.134
READY MIXES
Individual anesthesia practitioners, like good chefs, often have
their own recipes using fixed drug mixes for some clinical scenarios.
ketamine concentration (mg/L)
1
Probability of conciousness
0.5
P50
Propofol
0 0
0 60
Time (minutes)
ketamine concentration (mg/L)
1
Probability of conciousness
Ketamine
0.5
Propofol
0 0
0 60
Time (minutes)
Total Intravenous Anesthesia and Target-Controlled Infusion 197
These have the advantage of simplicity but lack the versatility of
separate infusions. Sterile infusions are prepared by the pharmacy
in some centers, although there can be reluctance to prepare such
infusions because of concerns about stability and the lack of
clinical studies documenting the safety and efficacy of these
mixtures. A common example used for endoscopy is shown in
8
Table 8.13.
Ketofol is a mixture of ketamine and propofol (1 : 1) that
is finding a niche for procedural sedation in the emergency
room.135 Stable hemodynamics, analgesia, and good recovery
are reported.136 The additive interaction for anesthesia induction
in adults has been reported.137 These data have been used to
simulate effect in children138; an optimal ratio of racemic ketamine
to propofol of 1 : 5 for 30 minutes of anesthesia and 1 : 6.7 for
90 minutes of anesthesia was suggested (Fig. 8.19).138 The “ideal
mix” for sedation will depend on the duration of sedation
and the degree of analgesia required. The CSHT of ketamine
increases with the duration of the infusion, resulting in delayed
recovery.139
ACKNOWLEDGEMENT
We wish to thank Neil Morton, Frank Ebers, Grace Lai-Sze Wong,
and James Limb for prior contributions to this chapter.
5
Propofol concentration (mg/L)
P95 3
2
FIGURE 8.19  The upper panel shows the probability of conscious-
Ketamine 1 ness during anesthesia using a propofol/ketamine ratio of 5 : 1. The
loading dose for induction of anesthesia was 2.5 mg/kg propofol and
0.5 mg/kg of ketamine.The infusion rate was 67% of that suggested
by McFarlan, Anderson, and Short18 for propofol alone. Ketamine
120 180 240 time-concentration profile is shown as a purple dotted line. Propofol
time-concentration profile is shown as a blue dotted line. The lower
panel shows simulation results for a 90-minute infusion. This panel
5 also shows the probability of consciousness as age increases from
a 2-year-old (solid blue line), to a 5-year-old (solid orange line), and
P95 a 10-year-old (green dashed line) child. The younger children have
Propofol concentration (mg/L)
4
greater clearance and regain consciousness earlier than older children.
P50 is the probability of consciousness in 50% of children; P95 is the
probability of consciousness in 95% of children. (From Coulter FL
3 Hannam JA, Anderson BJ. Ketofol simulations for dosing in pediatric
anesthesia. Pediatr Anesth. 2014;24:806-12. Used with permission.)
P50
2
120 180 240
198 A Practice of Anesthesia for Infants and Children
TABLE 8.13 A Recipe for Gastrointestinal Endoscopy Using a
Propofol-Remifentanil Mixture
Age >10 Years
50 µg remifentanil in 19 mL propofol (2.5 µg/mL remifentanil)
Start propofol mix at 175 µg/kg per minute
Age <10 Years
100 µg remifentanil in 18 mL propofol (5 µg/kg remifentanil)
Start propofol mix at 150 µg/kg per minute
If a higher remifentanil concentration is used in teenagers, then they
breathe at 2–4 breaths/minute and have systolic blood pressure of
approximately 75 mm Hg. If a lower remifentanil concentration is used,
they breathe at 8–10 breaths/minute and have a systolic blood
pressure of 76–84 mm Hg. Those aged <10 years generally do not
usually require any up or down change in the rate of infusion and
breathe at normal rates.
ANNOTATED REFERENCES
Absalom A, Amutike D, Lal A, et al. Accuracy of the “Paedfusor” in
children undergoing cardiac surgery or catheterization. Br J Anaesth.
2003;91:507-513.
The other widely used parameter set (children 1-15 years) programed into target-
controlled infusion pumps is the Paedfusor model. This parameter set is one of
the few whose performance has been validated.
Holford NHG, Sheiner LB. Understanding the dose-effect relationship:
clinical application of pharmacokinetic-pharmacodynamic models.
Clin Pharmacokinet. 1981;6:429-453.
This classic study explains use of the Hill equation to explain the concentration-
response relationship. The equation and its variants are used to relate both
vapors and drugs to anesthesia depth using such monitors as BIS.
Kataria BK, Ved SA, Nicodemus HF, et al. The pharmacokinetics of
propofol in children using three different data analysis approaches.
Anesthesiology. 1994;80:104-122.
Population modeling was used to determine a propofol parameter set in children
3 to 11 years. This parameter set is known as the Kataria model and is
programmed into many target-controlled infusion pumps.
Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender
on the pharmacokinetics and pharmacodynamics of remifentanil. I.
Model development. Anesthesiology. 1997;86:10-23.
This is an important study that characterized remifentanil pharmacokinetics in
adults. The parameter set is also used in children. There is an element of safety
with this approach because both volume of distribution and clearance decrease
with increasing age. The greater volume of distribution in children reduces the
peak concentrations of remifentanil after bolus dosing; the increased clearance
in children results in a smaller plasma concentration when infused at adult
rates expressed as milligrams per minute per kilogram.
Roberts FL, Dixon J, Lewis GT, et al. Induction and maintenance of
propofol anaesthesia. A manual infusion scheme. Anaesthesia.
1988;43(suppl):14-17.
The authors describe a manual infusion regimen for propofol that uses a decreasing
infusion rate change every 10 minutes to account for compartment kinetics. This
10-8-6 rule is still widely used and the principle has been adopted by others for
use in children administered drugs such as propofol, ketamine, and methadone.
Steur RJ, Perez RS, De Lange JJ. Dosage scheme for propofol in children
under 3 years of age. Paediatr Anaesth. 2004;14:462-467.
This analysis yielded one of the few infusion regimens available for neonates. Data
are limited in this age group, who are prone to an increased incidence of adverse
effects, and practitioners are advised to use caution with this technique. Dose-
response relationships for hypotension are lacking and the impact of postmenstrual
age on clearance and infusion regimens or combination therapy that retains
spontaneous respiration are awaited.
A complete reference list can be found online at ExpertConsult.com.

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